Apparatus and methods for treating tissue using passive injection systems

ABSTRACT

Methods and apparatus are provided for treating damaged tissue using apparatus that atraumatically delivers a bioactive agent within the tissue, wherein the apparatus provides a column of stem cells may be advanced simultaneously with a needle during needle insertion, and then held stationary or injected at low pressure while retracting the needle. Alternatively, the needle may employ electromotive forces, or to change a dimension of the needle, to expel the bioactive agent into the needle track.

REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/041,561, now U.S. Pat. No. 7,862,551, filed Mar. 3, 2008, which is acontinuation of U.S. patent application Ser. No. 10/977,594, now U.S.Pat. No. 7,338,471, filed Oct. 29, 2004, which is a continuation-in-partof U.S. patent application Ser. No. 10/894,810, now U.S. Pat. No.7,632,262, filed Jul. 19, 2004, the entire contents of all of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to apparatus and method for treating aninjured spinal cord and other injured tissue using passive injectionsystems that reduce barotrauma to the injected material and collateraldamage to the host tissue.

BACKGROUND OF THE INVENTION

Spinal cord injuries may arise from car accidents, violent crimes, fallsand sports injuries. Spinal cord injury is a major neurological problemsince most damage resulting from the injury is irreversible. Injurednerves fibers do not normally regenerate with resulting loss of nervecell communication, leading to paralysis and loss of sensation.

After spinal cord severance, a new glial basal lamina forms to cover theexposed surface of the cord end regions. The glial cells also secretebarrier molecules that are difficult to penetrate, further suppressingreestablishment of nerve interconnections. The spinal cord tissuebordering the severed region becomes necrotic, detaches from the spinalcord, and develops irregular cavities.

Most tissue in the human body originates from undifferentiated cellsknown as stem cells. These fundamental building blocks differentiateinto specific target parenchymal tissue based on hormonal and otherlocal signals. Scientific evidence suggests that stem cells injectedinto a target tissue will differentiate into a cell line specific to thehost tissue. This capability is of particular interest in treatingconditions involving organs, such as the spinal cord, heart and brainthat cannot regenerate.

Initial enthusiasm concerning stem cell implantation in patients wastempered by the ethical and logistic concerns of utilizing embryonicstem cells. Recent developments in stem cell research suggest adult stemcells can be harvested from the bone marrow and other tissues. Many such“cell lines” have been generated and are undergoing clinical evaluation.If successful, this work will obviate the moral and ethical dilemma ofutilizing tissue from embryos for research.

Pressurized direct injection of certain bioactive agents, such as stemcells, is expected to inflict physical damage to the cell membranes dueto fluid turbulence and pressure fluctuations (referred to herein as“barotrauma”) during the injection process. The damage may include lysisof the cells or injury to the cells that may significantly reduce theyield of viable cells delivered at the injection site and/or trauma tothe target tissue. Forceful injection of any material into tissue alsomay disrupt the delicate intercellular matrix, thereby causing targettissue cellular injury.

In view of these drawbacks of previously known apparatus and methods, itwould be desirable to provide methods and apparatus for treating severedor injured spinal cords by atraumatically delivering a bioactive agent,e.g., stem cells, within or adjacent to the injured spinal cord topromote nerve regeneration.

It would be also desirable to provide methods and apparatus for treatingspinal cord injury by delivering a bioactive agent so as to reduce therisk of barotrauma to the agent and target tissue during delivery.

It would be further desirable to provide apparatus and methods fortreating spinal cord injury by delivering a bioactive agent to damagedtissue to promote tissue regeneration, wherein the apparatus and methodsenhance the proportion of viable material delivered to the damagedtissue.

It further would be desirable to provide apparatus and methods fortreating a spinal cord injury to cause nerve regeneration of both thesensory and motor nerves in the spinal cord.

SUMMARY OF THE INVENTION

In view of the foregoing, it is an object of the present invention toprovide methods and apparatus for treating spinal cord injury or othernerve or muscle tissue by atraumatically delivering a bioactive agentwithin or adjacent to an injured portion of the nerve or muscle topromote regeneration.

It is another object of this invention to provide methods and apparatusfor treating spinal cord injury by delivering a bioactive agent so as toreduce the risk of barotrauma to the agent and target tissue duringdelivery.

It also is an object of this invention to provide apparatus and methodsfor treating spinal cord injury by delivering a bioactive agent todamaged tissue to promote tissue regeneration, wherein the apparatus andmethods enhance the proportion of viable material delivered to thedamaged tissue.

It is a further object of the present invention to provide apparatus andmethods for treating spinal cord injury to cause nerve regeneration ofboth the sensory and motor nerves in the spinal cord.

These and other objects of the present invention are accomplished byproviding methods and apparatus for delivering bioactive agents,preferably including stem cells or other precursor cells, to treatspinal cord injury, wherein the stem cells are delivered atraumatically.In the context of the present invention, “atraumatic” deployment meansdeployment of the stem cells without generating turbulent fluid motionthat inflicts physical damage to the stem cells, e.g., due to highshearing stresses or pressure fluctuations. The bioactive agentpreferably is delivered in a solution comprising nutrients to fosterstem cell survival after implantation, and one or more drugs or hormonesto suppress inflammatory response, etc.

In accordance with the principles of the present invention, thebioactive agent is directly deployed in a needle track formed in atarget tissue mass following formation of the needle track. In thismanner, the bioactive agent is not subject to barotrauma duringdelivery, nor does forceful impingement of the injectate during deliverydisrupt the pre-existing intercellular matrix.

Deployment of stem cells preferably is accomplished using needlearrangements that avoid impingement of the stem cells against targettissue at high velocity by employing low-pressure injection, capillaryaction or electrostatic forces to eject the stem cells out of the needleduring needle withdrawal. In one preferred embodiment, a column of stemcells may be advanced simultaneously with a needle during needleinsertion, and then held stationary while retracting the needle. Inanother embodiment the needle comprises an electroactive polymer thatcontracts along its length to expel the stem cells into the needletrack. In a further embodiment, electromotive forces are employed todeposit the stem cells into the needle track. According to someembodiments, a grid may be positioned over the injured portion of thespinal cord to guide injections of the bioactive agent.

While the present invention is described in the context of promotingregeneration of spinal cord tissue, the apparatus and methods of thepresent invention advantageously may be employed wherever it is desiredto promote tissue regeneration, such as in the heart, kidney, liver,brain and other organs and muscles.

Methods of using the apparatus of the present invention also areprovided.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features of the invention, its nature and various advantageswill be more apparent from the accompanying drawings and the followingdetailed description of the preferred embodiments, in which:

FIGS. 1A-1C are views depicting previously known methods of injectingdrugs and other bioactive agents into a tissue mass;

FIGS. 2A-2C are views depicting a method of injecting drugs and otherbioactive agents into a tissue mass in accordance with the principles ofthe present invention;

FIGS. 3A and 3B are views depicting apparatus of the present inventionfor injecting drugs and other bioactive agents into a tissue mass atmultiple sites simultaneously;

FIGS. 4A and 4B are, respectively, a side view, partly in section, andisolation view of the internal components of apparatus of the presentinvention;

FIGS. 5A-5C depict operation of the apparatus of FIG. 4;

FIGS. 6A and 6B are cross-sectional views of apparatus and methods ofthe present invention for injecting a bioactive agent into an injuredspinal cord;

FIGS. 7A and 7B are cross-sectional views of another embodiment of theapparatus of the present invention; and

FIGS. 8A and 8B are cross-sectional views of a further alternativeembodiment of apparatus of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Referring to FIGS. 1A-1C, some of the drawbacks of previously knownbioactive agent delivery systems are described. FIG. 1A illustrates apreviously known injection needle 10 being brought into approximationwith tissue mass T. Once the tip of needle 10 is inserted into thetissue, as shown in FIG. 1B, bioactive agent B, which may comprise stemcells, is injected into the tissue mass.

Applicant has discovered that pressurized injection of a bioactive agentmay have a substantial detrimental effect both on the agent deliveredand the tissue to be treated. For example, applicant has conductedstudies in which it had been observed that pressurized injection causesthe injectate stream to impinge violently against the tissue as itleaves the tip of the injection needle. During injection, the injectatestream is turbulent, and may experience rapid localized pressurefluctuations. These effects may damage the bioactive agent, particularlywhere the agent comprises stem cells, by rupturing the cell membrane orinjuring the cellular components.

In addition, as illustrated in FIG. 1C, once needle 10 has beenwithdrawn from the needle track N, the potential exists for the injectedbioactive agent B to be expelled from the needle track, with concomitantrisk of embolization. Applicant has concluded that a higher yield ofviable cells may be delivered to a target tissue if apparatus andmethods could be provided that reduce the effects of pressurizedinjection, including lysis and expulsion.

Referring now to FIGS. 2A to 2C, apparatus and methods of the presentinvention are described that overcome the drawbacks of previously knownsystems for delivering fragile bioactive agents, such as stem cells. Asshown in FIG. 2A, in accordance with the principles of the presentinvention, needle 20 is first approximated to spinal cord tissue mass T.In FIG. 2B, needle 20 is shown inserted into the tissue mass. In FIG.2C, as needle 20 is withdrawn from the tissue mass, bioactive agent B isdelivered from the tip of the needle and deposited in the needle track.

In accordance with the principles of the present invention, thebioactive agent is injected into the tissue under little pressure andwith substantially less turbulence and localized pressure fluctuationthan in previously known injection systems. Also, the bioactive agentwill not damage the tissue mass by splitting the tissue alongnaturally-occurring striations. These benefits of atraumatic injectionmay be particularly advantageous in the repair of an injured or severedspinal cord.

In FIGS. 3A and 3B, apparatus constructed in accordance with theprinciples of the present invention is described, in which distal end 25includes selectively extendable needles 26. As depicted in the Figures,needles 26 are configured to flare outward when extended beyond distalend 25 of the apparatus, thereby enhancing dispersal of the bioactiveagent into tissue mass T. As described above for the embodiment of FIG.2, needles 26 are configured to delivery bioactive agent B into thetissue mass while minimizing barotrauma to the bioactive agent and theinjury to the tissue mass. Although distal end 25 illustrativelyincludes three needles 26, a greater or lesser number of needles may beemployed without departing from the spirit of the present invention.

Referring now to FIGS. 4A and 4B, apparatus constructed in accordancewith the principles of the present invention is described. Apparatus 30comprises handle 31 that is configured to accept conventional syringe28, which may be loaded with a preselected bioactive agent, such as stemcells in a nutrient solution. The barrel of syringe 28 is removablycoupled to tube 32 via fluid-tight seal 33. Tube 32, which carries oneor more tissue-piercing needles at its distal end, is arranged toreciprocate through sleeve 34 so that the distal tip of the needleextends beyond bushing 35 when the device is actuated. Piston 29 ofsyringe 28 is removably coupled to block 36 and rails 37.

Handle 31 includes trigger 38 that may be depressed to selectivelyactuate apparatus 30. In particular, trigger 38 is coupled to tube 33via gear train 39 and linkage 40. Clamp 41 is configured to grip andreciprocate the body of the syringe in accordance with the degree ofactuation of trigger 38. Each of rails 37 preferably includes a portionthat forms a rack to permit forward movement of piston 29 of the syringeduring a first range of motion of trigger 38, and then retain piston 29stationary relative to rails 37 during a second range of motion of thetrigger.

Link 40 is coupled to clamp 41 so that, after syringe 28 and piston 29are advanced during the initial range of motion of the trigger, thepiston is held stationary while clamp 41 retracts tube 32 and needlesfrom the needle track(s) and simultaneously urges the body of syringe 28proximally. This motion causes the bioactive material within syringe 28to be dispensed into the needle track(s) (see FIGS. 2 and 3) at lowvelocity and with little or no barotrauma. As depicted in FIG. 4B (butomitted elsewhere for clarity), trigger 38 and link 40 preferably arebiased by springs 42 and 43, respectively, to return the mechanism toits starting position when trigger 38 is released.

Referring now also to FIGS. 5A-5C, operation of apparatus 30 isdescribed. In FIG. 5A, trigger 38 of the apparatus is shown at itsinitial position, and with syringe 28 and piston 29 in the proximal-mostpositions. As shown in FIG. 5B, as the trigger 38 is depressed abouthalf-way through its range of motion, gear train 39 and link 40 urgesyringe 28, piston 29 and rails 37 in the distal direction in unison.This in turn causes tube 32 and clamp 41 to be advanced distally, inturn causing needles 43 to extend beyond bushing 35. Illustratively, thetissue-piercing end of tube 33 includes three needles 43 that flareoutward upon entering into a tissue mass, as depicted in FIG. 3A.Because syringe 28 and piston 29 are moved in unison, the bioactiveagent contained within syringe 28 is subjected to substantially nohydraulic forces, and the distance between block 36 and theproximal-most portion of syringe 28 remains unchanged.

As further depicted in FIG. 5C, continued depression of trigger 38causes link 40 to begin retracting tube 32 in the proximal direction.This motion also drives clamp 41 in the proximal direction. Because therack portions of rails 37 disengage from link 40 and gear train 39during proximal movement of clamp 41, rails 37 and piston 29 remainstationary. Consequently, proximal movement of clamp 41 and tube 32 bothretracts needles 43 from the needle tracks formed in the tissue, andurges the body of syringe 28 against piston 29.

Still referring to FIG. 5C, proximal translation of clamp 41 also causesthe distance between block 36 and the proximal-most portion of syringe28 to shorten. This action applies sufficient pressure to the contentsof syringe 28 to dispense the bioactive agent into the needle tracksformed by needles 43 as the needles withdraw from the tissue. When theclinician releases trigger 38, springs 42 and 43 return tube 32 andclamp 41 to the starting position, shown in FIG. 5A. Apparatus 30 thenmay be repositioned, and the above process repeated.

As will be appreciated, the volume of injected material delivered intothe target tissue may be adjusted depending upon the target tissuemilieu. For example, for tissue or muscle that is fairly elastic, suchas heart muscle, additional material may be injected to createlow-pressure compartments within the tissue. On the other hand, lowervolumes may be employed in less resilient structures, such as the spinalcord and brain.

With respect to FIGS. 6A and 6B, in accordance with another aspect ofthe invention, needles 43′ of apparatus 30 may have differentpredetermined lengths so as to deliver the bioactive agent at variousdepths within spinal cord S to treat injured region D. As illustrated inFIG. 6A, needles 43′ may first be used to deliver bioactive agent on afirst side of a severed region D of spinal cord S, and then moved andapplied to the opposite side of the severed region (shown in dotted linein FIG. 6A). Additionally, needles 43′ may be arranged to beindividually rotated so that the bioactive agent is dispersed inpreselected directions.

FIG. 6B depicts the use of grid 50 to guide needles 43′ intopredetermined locations along spinal cord S. Grid 50 comprises block 51having a plurality of through holes 52 disposed along its surface toprovide a predetermined separation between injection regions.Advantageously, grid 50 lends structural support to damaged spinalregion D during stem cell injection. As in the method depicted in FIG.6A, apparatus 30 may be used to inject needles 43′ at a first location,and then repositioned using grid 50 (as shown in dotted line) to providesubsequent injections.

With further reference to FIG. 6, according to some methods of thepresent invention, a predetermined amount of cerebrospinal fluid may beremoved from spinal cord S prior to injecting the bioactive agent.Preferably, the amount of cerebrospinal fluid removed is substantiallyequivalent to the amount of bioactive agent, e.g., stem cell solution,injected into the spinal cord. This step of the method is expected toenhance atraumatic delivery of the bioactive agent by reducing the riskthat the injection prevents injury to the spinal artery or surroundingdelicate tissue during injection.

Referring now to FIGS. 7A and 7B, an alternative embodiment of aninjection needle constructed in accordance with the principles of thepresent invention is described. Needle 60 comprises a glass or polymermicrofiber adapted to receive and transmit electric signals, andincludes tissue-piercing distal end 61 and interior lumen 62. Needle 60is loaded with a bioactive agent, preferably comprising stem cells 65,and in addition is coupled to power supply 63 that applies an electricfield longitudinally along needle 60.

When energized by power supply 63, an electric field is applied toneedle 60 that attracts negatively charged stem cells 65 toward end 61,where they are deposited into the spinal cord. In particular, asdepicted in FIG. 7B, a positive charge is induced at distal end 61 ofneedle 60, thereby causing negatively charged stem cells 65 to be drawnto the distal tip of the needle.

Stem cells 95 are believed to be negatively charged in the naturalstate, so that they are drawn toward the positive charge at distal end61 of needle 60. Alternatively, an ionic solution containing negativelycharged particles may be added to the bioactive agent prior to injectionto increase the attraction of the stem cells towards a positive charge.The movement of stem cells 65 toward the positive charge causes apredetermined amount of the stem cells to be ejected from distal end 61into a target tissue mass, such as a damaged region of spinal cord.Needle 60 optionally may transmit a signal that defines a location ofthe needle when viewed using an MRI or CT device.

Referring now to FIGS. 8A and 8B, another alternative embodiment of thepresent invention is described. Needle 70 comprises an electroactivepolymer that forms an actuator, and includes tissue-piercing distal end71 and interior lumen 72. Needle 70 is loaded with a bioactive agent,preferably comprising stem cells 75, and is coupled to power supply 73that applies an electric field longitudinally along needle 70.Electroactive polymers are members of the family of plastics referred toas “conducting polymers,” and are preferred for the practice of thepresent invention due to their small size, large force and strain andlow cost.

In FIG. 8, injection needle 70 comprises an electroactive polymer thatis adapted to contract in response to electrical stimulation. Suitableelectroactive polymers include, but are not limited to, polypyrrole,polyacetylene, polyaniline and polysulfone. Oxidation or reduction ofthese polymers leads to a charge imbalance that results in a flow ofions (dopants) into the material in order to balance charge. The ionsenter the polymer from an ionically conductive electrolyte medium thatis coupled to the polymer surface. Conversely, if ions are alreadypresent in the polymer when it is oxidized or reduced, they may exit thepolymer.

Dimensional changes in electroactive polymers may be triggered by themass transfer of ions into or out of the polymer. For some electroactivepolymers, the expansion is due to ion insertion between chains, whereasrepulsion between chains is the dominant effect for other electroactivepolymers. The mass transfer of ions into and out of the electroactivepolymer leads to an expansion or contraction of the polymer. In thismanner, needle 70 may be contracted such that a predetermined amount ofbioactive agent is ejected from distal end 71 of the needle.

More specifically, needle 70 comprises an electroactive polymer that isconfigured to contract when an electric charge is applied to the needleby power supply 73. Needle 70 has a first diameter (FIG. 8A) and asecond, contracted diameter (FIG. 8B) when energized. Referring to FIG.8B, when an electrostatic charge is applied to injection needle 70, theneedle contracts and the diameter of lumen 72 decreases, therebyexpelling a predetermined amount of stem cells 75 out of distal end 71of needle 70. It is expected that constriction of lumen 72 is a bulkphenomenon that imposes a low-level distributed compressive force to thebioactive agent disposed in the lumen. Accordingly, substantiallysmaller local pressure fluctuations will be imposed on the bioactiveagent as compared to pressurized injection using a syringe, therebyreducing barotrauma and leading to substantially better viability of theimplanted stem cells.

As will of course be understood, the embodiments of FIGS. 7 and 8 mayinclude multiple needle tips to deliver bioactive agent at several sitesor depths simultaneously, and may be used with a grid, such as describedwith respect to FIG. 6, to deliver the bioactive agent according to apredetermined pattern. As will further be understood, power supplies 63and 73 of the embodiments of FIGS. 7 and 8, respectively, may includecontrollers that control operation of the electric fields applied to theneedles so that predetermined amounts of bioactive agent are deliveredby the needles when activated.

While preferred illustrative embodiments of the invention are describedabove, it will be apparent to one skilled in the art that variouschanges and modifications may be made therein without departing from theinvention. The appended claims are intended to cover all such changesand modifications that fall within the true spirit and scope of theinvention.

1-21. (canceled)
 22. A method of atraumatically depositing a bioactiveagent into a spinal cord, the method comprising: removing an amount ofcerebrospinal fluid from the spinal cord; and depositing an amount of abioactive agent into the spinal cord, wherein the amount ofcerebrospinal fluid is substantially equivalent to the amount of thebioactive agent.
 23. The method of claim 22, wherein the bioactive agentcomprises stem cells.
 24. The method of claim 23, further comprisingproviding a device for depositing the bioactive agent atraumaticallywithout inflicting barotrauma on the stem cells.
 25. The method of claim24, wherein the device comprises a first needle configured to depositthe amount of the bioactive agent.
 26. The method of claim 24, whereinthe device comprises: a first needle configured to deposit a firstportion of the amount of the bioactive agent substantially equivalent toa first portion of the amount of cerebrospinal fluid removed.
 27. Themethod of claim 26, wherein the device further comprises: a secondneedle configured to deposit a second portion of the amount of thebioactive agent substantially equivalent to a second portion of theamount of cerebrospinal fluid removed.
 28. The method of claim 27,wherein the first needle has a predetermined length different from apredetermined length of the second needle.
 29. The method of claim 28,wherein the depositing comprises depositing the first portion of the ofamount of the bioactive agent at a first depth within the spinal cord;and depositing the second portion of the of amount of the bioactiveagent at a second depth within the spinal cord, wherein the first depthis different from the second depth.
 30. The method of claim 27, whereinthe first and second needles are configured to deposit the bioactiveagent at substantially the same time.
 31. The method of claim 27,further comprising providing a grid having a block with a plurality ofthrough-holes, wherein a first through-hole is configured to receive thefirst needle and a second through-hole is configured to receive thesecond needle.
 32. The method of claim 31, further comprising, after thedepositing, repositioning the grid and then repeating the depositing.33. A method of atraumatically depositing a bioactive agent into aspinal cord, the method comprising: removing a first amount ofcerebrospinal fluid from a first side of the spinal cord; and depositinga first amount of a bioactive agent into the first side of the spinalcord, wherein the first amount of cerebrospinal fluid is substantiallyequivalent to the first amount of the bioactive agent.
 34. The method ofclaim 33, further comprising: removing a second amount of cerebrospinalfluid from a second side of the spinal cord; and depositing a secondamount of a bioactive agent into the second side of the spinal cord,wherein the second amount of cerebrospinal fluid is substantiallyequivalent to the second amount of the bioactive agent.
 35. The methodof claim 34, wherein the first side of the spinal cord is approximatelyopposite the second side of the spinal cord.
 36. The method of claim 34,wherein the first amount is different from the second amount.
 37. Themethod of claim 33, wherein the bioactive agent comprises stem cells.38. The method of claim 37, further comprising providing a device fordepositing the bioactive agent atraumatically without inflictingbarotrauma on the stem cells.
 39. The method of claim 38, wherein thedevice comprises: a first needle configured to deposit a first portionof the amount of the bioactive agent substantially equivalent to a firstportion of the amount of cerebrospinal fluid removed.
 40. The method ofclaim 39, wherein the device further comprises: a second needleconfigured to deposit a second portion of the amount of the bioactiveagent substantially equivalent to a second portion of the amount ofcerebrospinal fluid removed.
 41. The method of claim 40, furthercomprising: providing a grid having a block with a plurality ofthrough-holes, wherein a first through-hole is configured to receive thefirst needle and a second through-hole is configured to receive thesecond needle; positioning the grid adjacent to the first side of thespinal before depositing the first amount of the bioactive agent; andthen repositioning the grid adjacent to the second side of the spinalcord before depositing the second amount of the bioactive agent.